CN102091061B - Application of 1,2-diphenylethylene derivative in pharmacy - Google Patents
Application of 1,2-diphenylethylene derivative in pharmacy Download PDFInfo
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- CN102091061B CN102091061B CN 201010541715 CN201010541715A CN102091061B CN 102091061 B CN102091061 B CN 102091061B CN 201010541715 CN201010541715 CN 201010541715 CN 201010541715 A CN201010541715 A CN 201010541715A CN 102091061 B CN102091061 B CN 102091061B
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Abstract
The invention discloses novel application of a 1,2-diphenylethylene derivative, i.e. the 1,2-diphenylethylene derivative is used as a capsaicin receptor activated synergist. The 1,2-diphenylethylene derivative in the invention and a TRPV1 (Transient Receptor Potential Vanilloid) activator have a synergistic effect. The 1,2-diphenylethylene derivative can be used as the TRVP1 activated synergist and can be applied to the preparation of a pain-easing medicine preparation.
Description
Technical field
The present invention relates to the application of chemical compound in pharmacy, the application of stilbene derivant in pharmacy specifically.
Background technology
Capsaicin receptor (be transient receptor potential vanilloid receptor hypotype 1, be called for short TRPV1) is a kind of calcium ion to be had the non-selective cationic channel of high osmosis, and optionally high expressed is in nocuity sensory neuron [1].This receptor can be by capsaicin, hydrion (pH＜5.8), and the activation such as some inflammatory factor that produce when high temperature (＞43 ℃) and some endogenic ligands such as inflammation take place, this theory is considered to one of the main molecules mechanism of mediated pain [2].The main topological structure of TRPV1 is similar with Shaker associated voltage gate potassium channel, comprises that the N-terminal and the C-terminal and six that are present in the born of the same parents stride membrane structure, wherein strides the 5th and the 6th to have a formation district, hole [3] of lacking between the membrane structure.Discover that TRPV1 regulates at the upstream of many pain pathways, so TRPV1 becomes the novel targets of treatment pain.Capsaicin is found the earliest TRPV1 agonist.As the topical pain relief medicine, capsaicin is by the income American Pharmacopeia.Analgesic mechanism for the TRPV1 agonist generally has been considered to two kinds of situation at present, and (1) disposable heavy dose gives the TRPV1 agonist and causes the TRPV1 desensitization, thereby brings into play analgesic activity at short notice; (2) give high concentration TRPV1 agonist for a long time repeatedly and can open the TRPV1 passage on the one hand; Stream in calcium ion is a large amount of; Optionally cause the peripheral sensory neuron of having expressed TRPV1 because of the generation calcium intoxication, thus the performance analgesic activity, and meanwhile TRPV1 also can produce quick desensitization phenomenon.But research shows that heavy dose of capsaicin that uses can produce some untoward reaction, uses capsaicin to have burning sensation, can cause analgesia and various destructive stimuluses are lost reaction after a couple of days to several weeks like the part, and this is perhaps relevant with the desensitization phenomenon of TRPV1.In order to overcome the untoward reaction that the TRPV1 agonist is caused, people's expectation can be invented and a kind ofly can be produced synergistic medicine with the TRPV1 agonist, reduces the negative effect of TRPV1 agonist with this.
Summary of the invention
The object of the invention just provides a kind of exciting synergist of TRPV1 that has cooperative effect with the TRPV1 agonist.
The objective of the invention is to realize like this:
The invention provides a kind of new purposes of stilbene derivant, promptly activate synergist with the stilbene derivant as capsaicin receptor, this derivant has general formula shown in following (I):
Wherein R and R
1In be isothiocyano; Or one of them is isothiocyano, and another is nitro or acetylamino.
The more preferred chemical compound of the present invention is following listed particular compound
4,4 '-two isothiocyano stibene-2,2 '-its chemical structural formula of disulfonic acid (hereinafter to be referred as DIDS) is:
4-acetylaminohydroxyphenylarsonic acid 4 '-isothiocyano stibene-2,2 '-disulfonic acid (hereinafter to be referred as SITS), its chemical structural formula is:
DIDS, SITS are used as the blocker of chloride channel and some transporters for a long time, are widely applied in a lot of research fields.But never the someone finds that itself and TRPV1 agonist have synergism.The inventor finds after deliberation; DIDS and analog thereof itself do not have TRPV1 agonist effect; But itself and TRPV1 agonist share and can strengthen the ability that the TRPV1 agonist is opened the TRPV1 passage, can strengthen calcium ion and get interior flow, even can cancel the desensitization phenomenon of TRPV1; So it can accelerate the process that the nocuity neuron calcium is poisoned; Its effect has the dependent characteristics of TRPV1 agonist in addition, and its effect occurs over just the teleneuron that existence can cause the pain material, and is not all neurons that can touch.So can assert that stilbene derivant of the present invention and TRPV1 agonist have cooperative effect, it can be used as the exciting synergist of TRPV1 and in preparation analgesic preparation, is applied.
The compounds of this invention can exist with the form of free alkali or salt.Free alkali can be selected the mineral acid (example hydrochloric acid, sulphuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid), organic acid (like acetic acid, propanoic acid, citric acid, maleic acid, malic acid, tartaric acid, the methanesulfonic acid) salify that allow on the physiology when using.
Stilbene derivant provided by the invention is an active component with said stilbene derivant promptly as the application of capsaicin receptor activation synergist, and carrier or mixing diluents with pharmaceutically allowing to use are prepared into pharmaceutical preparation.Use in the lump with the TRPV1 agonist in use, under the situation that reduces TRPV1 agonist consumption, can obtain same analgesic effect thus.
Chemical compound according to the invention all can obtain from the commercial channel.
Indication of the present invention is acceptable carrier or diluent pharmaceutically, can be selected from excipient, adjuvant or solvent commonly used in the pharmaceutical preparation.Like lactose, sucrose, dextrin, Pulvis Talci, gelatin, agar, pectin, Radix Acaciae senegalis, magnesium stearate, stearic acid, cellulosic lower alkyl ether, corn starch, potato starch, natural gum, syrup, Oleum Arachidis hypogaeae semen, olive oil, phospholipid, fatty acid, fatty acid amine, glyceryl monostearate or glycerol disterate fat, coloring agent, correctives, antiseptic, water, ethanol, propanol, normal saline, glucose solution or the like.
Provided by the inventionly can carry out according to the preparation routine as the concrete method for preparing that capsaicin receptor activates synergist with the stilbene derivant.As can chemical compound according to the invention as active ingredient, be prepared into oral liquid with water, sucrose, Sionit, fructose etc.; Also can lactose, glucose, sucrose, mannitol sugar etc. be excipient, is disintegrating agent with starch etc., is lubricant with stearic acid, Pulvis Talci etc., gelatin, polyvinyl alcohol are that bonding agent is prepared into tablet or capsule; Also can be prepared into injection with the mixed carrier that normal saline, glucose solution or saline and glucose are formed.Also can be made into sterile powder injection and various slow releasing agent, suspensoid, Emulsion or the like.
When stilbene derivant of the present invention activates synergist and uses as capsaicin receptor, can also mass ratio be 1: 1 ratio, and be prepared into the external use plaster use after capsaicin mixes, can reduce by 50% capsaicin consumption thus.Detailed directions, consumption can be with reference to the capsaicin patches.
Synergist provided by the present invention can share alleviation and remove the pain that causes or bring out because of a variety of causes with the TRPV1 agonist.
Description of drawings
Fig. 1 is DIDS and capsaicin Combined application and the TRPV1 map of current of using DIDS separately.
Fig. 2 is that DIDS and capsaicin Combined application electric current increase the data statistics sketch map.
Fig. 3 is for merely repeatedly hanging down the pH extracellular fluid and in the TRPV1 of Combined application DIDS map of current.
Fig. 4 is that DIDS and low pH extracellular fluid Combined application electric current increase the data statistics sketch map.
Fig. 5 is for merely repeatedly hanging down the pH extracellular fluid and in the TRPV1 of Combined application SITS map of current.
Fig. 6 is that SITS and low pH extracellular fluid Combined application electric current increase the data statistics sketch map.
Fig. 7 be in HEK293 cell line DIDS to the potentiation of capsaicin.
Fig. 8 be in HEK293 cell line SITS to the potentiation of capsaicin.
Below in conjunction with accompanying drawing and specific embodiment the present invention is made further detailed description.
The specific embodiment
(1) test compounds DIDS: commercial DIDS CAS:207233-90-7 (Sigma lot number: 068K1116)
(2) method of testing: the adult SD rats (cultivation of 200～250g) Dorsal root neurons (DRG): get the whole dorsal root ganglion of adult SD rats; Collagenase, trypsinization; Containing 10% hyclone; Dispel in the DMEM culture fluid of 100U/ml penicillin and streptomycin, born of the same parents are laid on the circular lid slide of 12mm, and 24 orifice plates are cultivated.
Patch clamp technique record cell membrane electric current: patch clamp amplifier adopts Axon 700B.(final concentration 0.1～0.2mg/ml) is done punching patch-clamp record to use amphotericin B in the electrode.After the microelectrode polishing, liquid in the filling electrode, the controlling resistance value is at 1.5～2.5M Ω.The interior liquid of electrode used therein is (mM): KCl 150 during record DRG neuronal cell, and HEPES 10, MgCl
25, transfer pH to 7.4 with KOH; The extracellular fluid composition is (mM): NaCl 160, and KCl 2.5, and HEPES 10, glucose8, MgCl
21, CaCl
25.After microelectrode and cell membrane form huge resistance sealing-in, clamp down on after-80mV waits for 5-10min beginning and carry out the electric current record according to different stimulation programs.
(3) test result: as can beappreciated from fig. 1, associating application 1 00 micromole DIDS can increase the TRPV1 current amplitude that capsaicin causes on the capsaicin basis.Can not cause the TRPV1 current amplitude and use DIDS separately.The electric current that DIDS and capsaicin Combined application can make capsaicin cause increases 2.16 ± 0.13 times (seeing Fig. 2 for details).
(1) test compounds: DIDS
(2) method of testing: with embodiment 1 method therefor
(3) test result: as shown in Figure 3, the extracellular fluid that employing-60mV continuous record mode record repeatedly gives pH=5 activates the TRPV1 passage, and there is obviously desensitization phenomenon fast in the TRPV1 electric current.Associating application 1 00 micromole DIDS can increase the TRPV1 electric current on the extracellular fluid basis of pH=5, and has blocked the quick desensitization phenomenon of TRPV1 electric current.DIDS and low pH Cell sap Combined application can cause electric current and increase 4.48 ± 0.69 times (seeing Fig. 4 for details).
Chemical compound according to the invention source all can obtain from the commercial channel, in the concrete source of chemical compound described in the biological activity determination embodiment of chemical compound is DIDS CAS:207233-90-7 (Sigma lot number: 068K1116);
(1) test compounds SITS, (SITS CAS:51023-76-8 (Sigma lot number: 107K1065)) is buied in market
(2) method of testing: with embodiment 1 method therefor
(3) test result: the extracellular fluid that employing-60mV continuous record mode record repeatedly gives pH=5 activates the TRPV1 passage, and there is obviously desensitization phenomenon fast in the TRPV1 electric current; Use SITS separately and can not cause the TRPV1 electric current; Associating application 1 00 micromole SITS can increase TRPV1 electric current (as shown in Figure 5) on the extracellular fluid basis of pH=5.SITS and low pH extracellular fluid Combined application can cause electric current and increase 4.21 ± 0.68 times (seeing Fig. 6 for details).
The electric physiology patch-clamp of embodiment 4 are measured: SITS the potentiation of capsaicin in HEK293 cell line.
(1) test compounds: DIDS, SITS
(2) method of testing: human embryonic kidney cell's (HEK 293A) cultivation: adopt the HEK 293A cell culture that Lipofectamine 2000reagent (Invitrogen) wink has changeed rat TRPV1 passage in containing 10% hyclone; In the DMEM culture fluid of 100U/ml penicillin and streptomycin, trypsinization is gone down to posterity.Cell is laid on the circular lid slide of 12mm, 24 orifice plates are cultivated
Patch clamp technique record cell membrane electric current: patch clamp amplifier adopts Axon 700B.(final concentration 0.1～0.2mg/ml) is done punching patch-clamp record to use amphotericin B in the electrode.After the microelectrode polishing, liquid in the filling electrode, the controlling resistance value is at 1.5～2.5M Ω.Liquid is (mM): KCl 150 in the record electrode used therein, and HEPES 10, MgCl
25, transfer pH to 7.4 with KOH; The extracellular fluid composition is (mM): NaCl 160, and KCl 2.5, and HEPES 10, and glucose 8, MgCl
21, CaCl
25.After microelectrode and cell membrane form huge resistance sealing-in, clamp down on after-80mV waits for 5-10min beginning and carry out the electric current record according to different stimulation programs.
(3) test result: associating application 1 00 micromole DIDS can increase the TRPV1 current amplitude (as shown in Figure 7) that capsaicin causes on the capsaicin basis, and the result is with consistent in the neuronic result of DRG.Combined application SITS can not increase the TRPV1 electric current (as shown in Figure 8) that capsaicin causes on the capsaicin basis.Explain that thus SITS has specific potentiation to the hydrion agonist.
Take by weighing DIDS 100g, capsaicin 100g, mix homogeneously with reference to the conventional method for preparing of plaster preparation, prepares the plaster preparation that every subsides contain the 5mg capsaicin.
Prepare tablet according to methods known in the art, every contains following compositions:
DIDS 25mg
Lactose 70mg
Magnesium stearate 5mg
Polyethylene is than pyrrolidone 100mg
Above embodiment is in order to illustrate in greater detail the present invention, but it does not limit the present invention in any form.
Claims (4)
1.2-diphenyl ethylene derivatives activates the application in the synergist at the preparation capsaicin receptor, this derivant has general formula shown in following (I):
Wherein R and R
1Be isothiocyano; Or one of them is isothiocyano, and another is nitro or acetylamino.
2. stilbene derivant according to claim 1 activates the application in the synergist at the preparation capsaicin receptor, it is characterized in that with said 1; The 2-diphenyl ethylene derivatives is 4; 4 '-two isothiocyano stibene-2,2 '-disulfonic acid, its chemical constitution is:
3. according to claim 11; The 2-diphenyl ethylene derivatives activates the application in the synergist at the preparation capsaicin receptor, it is characterized in that with said stilbene derivant be 4-acetylaminohydroxyphenylarsonic acid 4 '-isothiocyano stibene-2; 2 '-disulfonic acid, its chemical constitution is:
4. according to claim 2 or 3 described 1; The 2-diphenyl ethylene derivatives activates the application in the synergist at the preparation capsaicin receptor, it is characterized in that with said stilbene derivant be active component; Carrier or mixing diluents with pharmaceutically allowing to use are prepared into pharmaceutical preparation.
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| CN 201010541715 CN102091061B (en) | 2010-11-12 | 2010-11-12 | Application of 1,2-diphenylethylene derivative in pharmacy |
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| CN 201010541715 CN102091061B (en) | 2010-11-12 | 2010-11-12 | Application of 1,2-diphenylethylene derivative in pharmacy |
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| JP6835815B2 (en) * | 2015-07-17 | 2021-02-24 | アレス トレーディング ソシエテ アノニム | How to modify the production profile of recombinant proteins |
| CN114288282B (en) * | 2021-12-28 | 2023-06-23 | 庹必光 | Application of 4,4 '-diisothiocyano stilbene-2,2' -disulfonic acid in preparation of medicines for preventing and/or treating obesity |
| CN116217611B (en) * | 2023-05-10 | 2023-07-11 | 成都摩诃大龙医药科技有限公司 | Cyclobutanone derivative, preparation method and application |
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| CN1890223A (en) * | 2003-10-31 | 2007-01-03 | 神经能质公司 | Capsaicin receptor agonists |
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